PK/PD modeling of a clazosentan thorough QT study with hysteresis in concentration-QT and RR-QT

AbstractClazosentan's potential QT liability was investigated in a thorough QT study in which clazosentan was administered intravenously as a continuous infusion of 20  mg/h immediately followed by 60 mg/h. Clazosentan prolonged the placebo-corrected change-from-baseline QT interval corrected for RR with Fridericia's formula (ΔΔQTcF) with the maximum QT effect occurring 4 h after the maximum drug concentration, apparently associated with vomiting. The delayed effect precluded the standard linear modeling approach. This analysis aimed at characterizing the concentration-QT relationship in consideration of RR-QT hysteresis, concentration-ΔΔQTcF hysteresis, and the influence of vomiting. Nonlinear mixed-effects modeling was applied to characterize pharma cokinetics and pharmacodynamics, i.e., ΔΔQTcF. Simulations were used to predict ΔΔQTcF for expected therapeutic dose used in Phase 3 clinical development. Correction for RR-QT hysteresis did not influence ΔΔQTcF to a relevant extent. Pharmacokinetics of clazosentan were best described by a lin ear two-compartment model. The delayed QT prolongation was characterized by an indirect-response model with loglinear drug effect. Vomiting had no statistically significant influence on QT prolongation despite apparent differences between subjects vomiting and not vomiting, probably since vomiting o ccurred mostly after the main QT prolongation. Following a simulated 3-h infusion of 15 mg/h of clazosentan, the upper bound of ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - Category: Drugs & Pharmacology Source Type: research